Fedotozine (prop. INNM) is (+) (R)-1-[(3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N, N-dimethyl-n-propylamine which, when salified with (2s, 3s)-(-) tartaric acid, is represented by the formula below: ##STR1##
The compound modifies the digestive motilities, acting by a mechanism that involves the peripheral opiate receptors, notably those of the kappa (.kappa.) type.
In European patent application No 0 384 088 it is shown that in vitro, the product shows a non-specific affinity for the opioid receptors, especially those of the mu and the kappa types. In vivo in mice it shows almost no analgesic effect when administered orally in the "writhing test" carried out as described by Koster. When administered orally to dogs it is found to stimulate the gastric drainage, and this led to the proposal that it should be used in man for the same application and to regularize the gastro-intestinal transits.
Furthermore, X. Pascaud et al. (J. Pharm. Pharmacol. 1990, 42: 546-62) have shown that apart from its stimulant activity at the level of the gastric antrum, in dogs the compound also has a stimulant action at the level of the small intestine and the colon.
These properties have been applied or proposed in man for the treatment of motility dysfunctions at various levels of the tract such as the gastro-oesophagal reflux (Bost, R. et al., Eur. J. Gastroenterol. Hepatol/1991, 3, S 13), dyspeptic conditions (Homerin, M. et al., World Cong. Gastroenterol. [Aug. 26-31, Sydney] 1190, Abst. PP 455) and motor atonicity of the small intestine (Karaus, M. et al., J; Gastrointest. Motil. 1991, 3: A186).
More recently, the present applicant has shown that when fedotozine (-) tartrate is administered to rats via the intravenous (i.v.) or subcutaneous (s.c.) routes, it restores the tonus and motility in an experimental adynamic ileus at the gastric and jejunal levels, and globally throughout the gastrointestinal tract. This use is disclosed in U.S. patent application Ser. No. 07/937,127, filed Aug. 31, 1992.
Finally, using healthy volunteers and a clinical-pharmacological model close to the latter symptomatology, which consisted in inducing a pseudo-obstructive distention at the gasric level, B. Coffin et al. (Gastroenterology, 1992, 102, 4, Apr., A437) found that (-) fedotozine tartrate reduced the sensation of discomfort in the subjects.
It is generally accepted that analgesic compounds are symptomatic medicaments that reduce or abolish painful sensations but without acting on the algogenic phenomenon, whose nature can vary (inflammation, muscular or visceral spasm, focus of infection, cancer, etc.) and can be of central or peripheral origin. Among such compounds the agonistic opiates, of which morphine is a typical representative, have known effects. Since the studies of Martin, who in 1976, under the heading of the opioid receptor class identified three types known as mu (.mu.), delta (.delta.) and kappa (.kappa.), a very large number of investigations have attempted to define the roles and the respective involvements of those receptors in the physiology of life, and to prepare new agonistic or antagonistic ligands for them. In particular, one aim of research has been to prepare new compounds with analgesic activity of a power comparable with that of morphine, but exempt from its addictive side effects. To this end, numerous compounds showing affinity and marked selectivity for the various opioid receptors have been designed and synthesized. The most remarkable among these are agonistic and/or antagonistic .mu. and .kappa. receptor ligands, and these have been proposed for the treatment of various painful conditions as described in a review of the subject by E. Freye (Drugs of Today, Vol. 25, No 11, 1989, pp. 741-754).
On examining the pharmacological and clinical side effects of these compounds, it became apparent and established that apart from their analgesic action the .mu. agonists induce states of euphoria, a slowing-down of the gastro-intestinal transit, respiratory depression, habituation and addictive physical dependence, whereas with the .kappa. agonists the phenomena observed were essentially sedation, tolerance and diuretic effects, phenomena regarded as less serious than those induced by the .mu. agonists.
This consideration has motivated special interest in the search for .kappa.-agonist analgesics, with efforts to improve them and to minimise their mainly sedative and diuretic side effects. The state of this work was reported in 1988 by David C. Horwell (Drugs of the Future, Vol. 13, No 12, 1988, pp. 1061-1071).
At present the .kappa. agonists are still considered to represent a step forward in the treatment of pain (SCRIP, No 1697, 1992, p. 22). Thus, they are regarded by some as the first new class of analgesics developed for many years.
In contrast to the majority of opioid analgesics developed, which are not selective and interact with the .mu. or .delta. receptors that probably mediate undesirable effects, it was hoped that specific .kappa. agonists would be exempt from these effects, especially the addictive ones. However, the compounds obtained so far only partially respond to that aim. In fact, all of them, to varying extents, show the familiar disadvantages, namely sedative and diuretic effects, the latter in particular having been observed in clinical trials or pharmacological studies with compounds considered to be reference .kappa. agonists such as U-50,488H and PD-117302 that are representative of the chemical category of arylacetamides.
Similarly, the development of certain products that are less selective towards the .kappa. receptors, such as bremazocine, was interrupted because of their capacity to induce modifications of the mental condition or behavioural changes.
Recently, J. Hughes and G. N. Woodruff have reviewed the state of the subject ("Neuropeptides", Arzneim.-Forsch. 42 (6) 2a (1992), p. 250). They state that for a long time there has been considerable interest in the possibility of inducing analgesia via the .kappa. receptors as an alternative solution to treatment via the type-.mu. opiates. The .kappa. receptors are localized at the sites concerned with the process and transmission of nociceptive information (substantia gelatinosa, thalamus, periaqueductal grey matter, -monoaminergic neurons). In tests carried out with animals the .kappa. agonists are antinnociceptive agents and are more effective against the reflexes induced by pressure and chemical stimuli than by the tests provoked by heat (Przelocki 1987). They are particularly effective against inflammatory pains (Haley et al. 1990).
Apart from the potential reduction of tolerance and physical dependence risks, the .kappa. agonists have the advantage of inducing only minimum respiratory depression and having no constipatory effects. However, all compounds of this category tested in man have induced a range of subjective effects (Horwell 1988) and, at the present state of research, none of those studies has succeeded in discovering a .kappa.-agonist compound that is truly selective and that possesses a large enough margin between the analgesic effect sought and the undesirable side effects, whether subjective or objective, the most evident of which are the sedative and diuretic effects.